Source: Health Products and Food Branch (CA) Revision Year: 2014
Loxapine, a tricyclic dibenzoxazepine antipsychotic agent, which is clinically distinct from the phenothiazines, thioxanthenes and butyrophenones, produces pharmacologic responses in various animal species which are characteristic of those seen with the majority of antipsychotic drugs.
LOXAPAC IM is an antipsychotic drug which exhibits many of the actions common to this broad class of drugs. LOXAPAC IM has proven to be of value in the management of both acute and chronic schizophrenia. As in the case of other antipsychotics, the mode of action has not been clearly established, but is postulated to involve changes in synaptic transmission at the subcortical level of the brain, resulting in strong inhibition of spontaneous motor activity.
Loxapine appears to act by reducing the firing thresholds of CNS neurons acting in polysynaptic pathways, particularly those in the reticular formation.
Signs of sedation in normal volunteers appear generally within 30 minutes for oral and parenteral administration. Duration of sedation is essentially the same with either the tablets or the oral concentrate and may last through a 12-hour period. The duration and intensity of sedation produced by the intramuscular formulation in normal volunteers have been less than those observed following oral administration. (Average: one hour with the intramuscular solution and close to three hours with the oral administration). When multiple doses were given by the oral or intramuscular route, the onset and duration of sedative effects were generally comparable. Initially, sedation occurred within 1.5 hours of the dose and lasted 8 hours: thereafter the duration was shortened to 1-2.5 hours.
The drug does not appear to have antidepressant or anticonvulsant activity and may lower the seizure threshold. In addition, in patients with a history of seizure disorders, generalized tonicclonic (grand mal) seizures have been associated with usual therapeutic doses of loxapine (see WARNINGS AND PRECAUTIONS, Neurologic).
Absorption of orally administered loxapine tablets, oral concentrate, and intramuscular injection in man is rapid and virtually complete following a single 25 mg dose. After administration of the oral concentrate somewhat higher and earlier peak serum levels may be expected initially than after tablet administration. When the intramuscular administration was compared to the oral administration, the mean serum concentrations of unmetabolized loxapine were approximately twice as high after intramuscular injection of 25 mg as they were after equivalent oral dosage during the period of 1 to 4 hours.
Animal studies with radioactive drug indicate that loxapine and/or its metabolites are widely distributed in body tissues with highest concentrations in brain, lungs, heart, liver, and pancreas. The drug appears in the cerebrospinal fluid. Although no human data are available, animal studies indicate that loxapine crosses the placenta and distributes into milk.
Loxapine is metabolized extensively, essentially no unchanged parent drug being excreted in urine or feces. The serum half-life of loxapine is approximately 3 hours. The serum concentration time curve of total drug-related materials (loxapine plus metabolites), as shown by studies with radio-labelled drug, is biphasic in nature and shows larger half-lives, i.e. five hours for the alpha-phase and 19 hours for the beta-phase.
Five metabolites have been identified in the urine – loxapine N-oxide, 8-hydroxyloxapine, 7-ydroxyloxapine, 8-hydroxyamoxapine and 7-hydroxyamoxapine. The phenolic metabolites are excreted in the urine largely in the form of conjugates and in the feces primarily in the free form. In man, the greater proportion of the dose (56-70%) is excreted in the urine.
Many of the actions of loxapine in various animal species are characteristic of those seen in the majority of antipsychotic drugs. Loxapine administration results in a strong inhibition of spontaneous motor activity. It has shown a marked cataleptic action and is intensely antagonistic to the stereotyped activities of both d-amphetamine and apomorphine. Loxapine also protects mice against the lethal actions of d-amphetamine at low doses and completely inhibited the emetic action of apomorphine in dogs at doses of 0.125 to 2.0 mg/kg when administered intraperitoneally. The drug has further shown an inhibitory effect on conditioned avoidance. In unanesthetized rabbits and cats fitted with chronically implanted electrodes, loxapine was shown to produce high amplitude slow waves in the cerebral cortex, along with occurrence of spikes which were synchronized in all leads. The drug has no anticonvulsant properties; on the contrary, EEGs showed that 5 mg/kg initiated electrogenic seizure patterns and postictal electrical depression. There was a tendency to dissociation between cortical EEG and hippocampal EEG – a phenomenon not usually seen in antipsychotic drugs.
In these same animal preparations, loxapine acted as a stimulator of the amygdala and hippocampus and did not inhibit seizure discharge in these areas. It is postulated that this occurs through the inhibition of the normal inhibitory mechanisms operating in these areas of the brain.
The drug exhibited an inhibitory effect on the arousal response of the posterior hypothalamus when this locus was stimulated, and exhibited a similar but milder effect on the midbrain ascending reticular formation.
In a special cat preparation, loxapine facilitated polysynaptic spinal reflex potentials and had a similar effect on the subcortical sensory reception area.
In dosages which significantly reduced motor activity in mice, the administration of loxapine resulted in decreases in the total brain concentration of dopamine, but yielded no alteration of norepinephrine levels and showed no effect on 5-HT levels.
Cardiovascular effects of loxapine such as hypotension and ECG changes, as well as respiratory effects, are mild to moderate and are transient in the therapeutic dose range. In the whole anesthetized cat, or rabbit, no appreciable atropine-like or adrenolytic effect was noted. Loxapine when administered alone was found to be mildly diuretic.
Loxapine has been shown to decrease the vasopressor effect of epinephrine and phenethylamine, but not that of norepinephrine or angiotensin nor the depressor response of isoproterenol.
Chlorpromazine and diazepam were found to be synergistic with loxapine as depressants of locomotor activity, with diazepam apparently having a greater effect. The enhancement of the duration of hypnosis with pentobarbital, ethanol and meprobamate should also be noted. There is no apparent effect of loxapine on the anticonvulsant actions of diphenylhydantoin and no apparent interaction with imipramine.
Absorption following orally administered loxapine succinate is virtually complete. There is a peak in mean serum concentration of total radioactivity at two hours after dosing with labelled loxapine. In animal studies, the tritium labelled drug has been shown to be removed rapidly from the plasma, the preferential distribution being in lungs, brain, pancreas, spleen, heart, kidney and liver. The liver concentration consisted largely of metabolized drug.
The onset of pharmacologic effects is usually apparent within 15 to 30 minutes after oral, intramuscular, intravenous or subcutaneous administration to the rat, after oral, intramuscular and intraperitoneal administration to the dog and monkey, and after intraperitoneal administration to the cat. The peak effect was generally reached in one to three hours, and the duration of activity ranged from four to six hours. With higher doses, the duration of action was more prolonged.
Loxapine is metabolized extensively in animals and human and excreted both in the urine and feces. There appear to be three reactions, other than phenol conjugation, involved in the metabolism of loxapine: aromatic hydroxylation, N-oxidation and N-demethylation. Unmetabolized drug has not been recovered in urine and feces, though metabolites are excreted in urine mainly in the form of conjugates and in feces mainly in the unconjugated form.
In rats, 86% to 96% of orally administered doses of radiolabelled loxapine has been recovered in urine and feces. In dogs, 92% to 104% has been similarly recovered. Approximately one half of the drug is recovered within the first 24 hours.
Acute LD50 doses of orally administered loxapine in mice and rats are, respectively, 65 and 40 mg/kg. The LD50 of loxapine parenteral after intravenous administration to mice is 17.4 mg/kg. In dogs, single oral doses of 5 to 10 mg/kg induced decreased locomotor activity, catatonia and sedation. Extrapyramidal signs appeared with increasing severity at doses of 20 to 50 mg/kg. Doses of 60 mg/kg caused premonitory signs of convulsions: higher doses (90-120 mg/kg) caused convulsions and mortality.
In chronic toxicity studies over a 19-month period of diet administration of loxapine to rats (0.23-5.57 mg/kg/day), the major toxic signs observed were the reduction in food and water intake and decreased body weight gain. There were no significant clinical or post-mortem drugrelated findings. In dogs dosed daily for one year with 1 to 30 mg/kg of loxapine, the most prominent clinical findings were sedation, miosis and ptosis. There were no drug-related findings in either species.
The effect of loxapine up to 1.7 mg/kg/day on fertility and general reproductive performance in rats consisted of reduction in food consumption and body weight gain of males and females fed drug during the pre-mating period, reduction in the percentage of copulating pairs and, at the high dose, the absence of coitus. Examination of vaginal smears during mating showed females which failed to copulate to be in continuous diestrus. Re-mating of treated males with non-treated females failed to demonstrate any antifertility effect in males.
Oral administration of loxapine (1-12 mg/kg/day) to pregnant mice and rats during the period of organogenesis resulted in an increase in fetal resorptions. No teratogenic potential was demonstrated.
Administration of loxapine up to 1.86 mg/kg/day to rats from day 16 of pregnancy up to weaning resulted in parturition difficulties in some rats, in increased neonatal mortality and in generalized growth retardation of the pups, characterized by reduced pup weight, retarded kidney development and delayed skeletal ossification. Administration of chlorpromazine produced similar findings. Kidney and skeletal development and weight of surviving offspring from rats that received loxapine were comparable to controls by the middle of the lactation period.
Oral administration of loxapine to the rabbit at doses up to 0.8 mg/kg/day 10 days before the first mating and through three reproductive cycles produced no changes in fertility, reproduction, or lactation and did not affect embryonal or fetal development.
In a teratology study with New Zealand white rabbits, no embryotoxic or fetotoxic effects which could be attributed to treatment were observed in fetuses from dams treated by intramuscular injection with doses of 2.5, 5.0 and 10.0 mg/kg/day (1.25, 2.5 and 5.0 mg/kg twice daily) of loxapine base on gestation days 6 through 18. In animals treated orally with 10 mg/kg/day (5 mg/kg calculated as base, twice daily) of loxapine succinate, two fetuses with multiple malformations from separate litters exhibited exencephaly and three fetuses from a third litter had internal hydrocephaly.
In a teratogenic study in the beagle dog, intramuscular doses of 5 or 10 mg/kg/day (2.5 or 5.0 mg/kg twice daily) loxapine, or oral doses of 10 mg/kg/day (5 mg/kg twice daily) of loxapine succinate, were administered on gestation days 14 through 38. Postnatal survival of offspring from littering dams was markedly reduced in all drug treated groups for the first week following parturition. No teratogenic effects due to treatment were demonstrated.
In previous teratology studies with loxapine succinate, oral doses up to 10 mg/kg/day were administered to brown rabbits for gestation days 6 through 18 and to beagle dogs for gestation days 18 through 39. In these studies, no teratogenic or other embryotoxic or fetotoxic effects were observed in the offspring of treated animals which could be attributed to treatment with loxapine succinate.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
